A 20 to 30 percent excess of males among the mentally retarded population is well documented. At least half of the excess is likely due to mutations of X-linked genes. An estimated 30-40 loci are associated with nonsyndromic X-linked mental retardation (XLMR) and one hundred thirty are associated with specific XLMR syndromes. The best known of these is the Fragile X syndrome but it accounts for only a third of XLMR families. Because of the X-linked mode of inheritance and current molecular methodologies, these disorders are especially amenable to study. The hypothesis to be tested is that a full understanding of the genetics and pathogenesis of these disorders will lead to improved diagnosis and (ultimately) therapy. The immediate goal of the study is to identify the causative genes and the genetic pathways leading to XLMR. In addition, we will better define the clinical and neurobehavioral phenotypes of these disorders, each of which presents unique aspects about brain development and function. Over the last ten years, 55 large XLMR families and 68 smaller families have been admitted to the study for gene localization, gene testing and neurobehavioral studies. Thirty-two of the families have been localized to a discrete region of the X chromosome. In addition to these families, 2 males with inversions of the X chromosome associated with mental retardation and 3 males with small deletions are available for molecular studies. We have deposited brains from three XLMR study families are in the Miami Brain Bank and will utilize them for both molecular studies and comprehensive histological analysis. Three new investigators, (Srivastava, Inana, and Warren) have joined the study. A variety of appropriate microarray systems, subtractive cDNA and other appropriate methods (including maximal utilization of the new human genorne data) will be used to identify and characterize ten to fifteen XLMR genes over the next five years. We will continue to admit five new families and a number of smaller families each year. Neurobehavioral studies will be closely integrated into the clinical evaluation of each of the new large families. More extensive neurobehavioral studies along with MRI morphometric analysis will be conducted in three XLMR entities: Coffin-Lowry, ATRX and Allan-Herndon Syndrome. In summary, this represents a unique study that combines a variety of methodologies and disciplines in order to better understand the role of genes on the X chromosome in brain development and function.